Publications by authors named "J Y Scheele"

225 Publications

Phase 1b/2 trial of tepotinib in sorafenibpretreated advanced hepatocellular carcinoma with MET overexpression.

Br J Cancer 2021 Apr 6. Epub 2021 Apr 6.

Medical Oncology, Saint-Louis Hospital & Paris 7 University, Paris, France.

Background: This Phase 1b/2 study evaluated tepotinib, a highly selective MET inhibitor, in US/European patients with sorafenibpretreated advanced hepatocellular carcinoma (aHCC) with MET overexpression.

Methods: Eligible adults had aHCC, progression after ≥4 weeks of sorafenib, and, for Phase 2 only, MET overexpression. Tepotinib was administered once daily at 300 or 500 mg in Phase 1b ('3 + 3' design), and at the recommended Phase 2 dose (RP2D) in Phase 2. Primary endpoints were dose-liming toxicities (DLTs; Phase 1b) and 12-week investigator-assessed progression-free survival (PFS; Phase 2).

Results: In Phase 1b (n = 17), no DLTs occurred and the RP2D was confirmed as 500 mg. In Phase 2 (n = 49), the primary endpoint was met: 12-week PFS was 63.3% (90% CI: 50.5-74.7), which was significantly greater than the predefined null hypothesis of ≤15% (one-sided binomial exact test: P < 0.0001). Median time to progression was 4 months. In Phase 2, 28.6% of patients had treatment-related Grade ≥3 adverse events, including peripheral oedema and lipase increase (both 6.1%).

Conclusions: Tepotinib was generally well tolerated and the RP2D (500 mg) showed promising efficacy and, therefore, a positive benefit-risk balance in sorafenibpretreated aHCC with MET overexpression.

Trial Registration: ClinicalTrials.gov: NCT02115373.
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http://dx.doi.org/10.1038/s41416-021-01334-9DOI Listing
April 2021

Tepotinib plus gefitinib in patients with EGFR-mutant non-small-cell lung cancer with MET overexpression or MET amplification and acquired resistance to previous EGFR inhibitor (INSIGHT study): an open-label, phase 1b/2, multicentre, randomised trial.

Lancet Respir Med 2020 11 29;8(11):1132-1143. Epub 2020 May 29.

National Taiwan University Hospital, Taipei, Taiwan.

Background: We evaluated the efficacy and safety of tepotinib, a potent and highly selective oral MET inhibitor, plus gefitinib in patients with epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) with MET overexpression (immunohistochemistry [IHC]2+ or IHC3+) or MET amplification having acquired resistance to EGFR inhibition.

Methods: In this open-label, phase 1b/2, multicentre, randomised trial (the INSIGHT study), we enrolled adult patients (≥18 years) with advanced or metastatic NSCLC, and Eastern Cooperative Oncology Group performance status of 0 or 1, from academic medical centres and community clinics in six Asian countries. In phase 1b, patients received oral tepotinib 300 mg or 500 mg plus gefitinib 250 mg once daily. In phase 2, patients with EGFR-mutant, T790M-negative NSCLC MET overexpression or MET amplification were randomly assigned (initially in a 1:1 ratio and then 2:1 following a protocol amendment) to tepotinib plus gefitinib at the recommended phase 2 dose or to standard platinum doublet chemotherapy. Randomisation was done centrally via an interactive voice-response system. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS) and safety. Subgroup analyses were preplanned in patients with high MET overexpression (IHC3+) or MET amplification (mean gene copy number ≥5 or MET to centromere of chromosome 7 ratio ≥2). Efficacy and patient characteristics were assessed on an intention-to-treat basis and safety was assessed for all patients who received at least one dose of study medication. Low recruitment led to early termination of phase 2, so all analyses are considered to be exploratory. This study is registered with ClinicalTrials.gov, NCT01982955, and the European Union Drug Regulating Authorities Clinical Trials Database, Eudra-CT 2016-001604-28.

Findings: From Dec 23, 2013, to May 25, 2017, 18 patients were enrolled in phase 1b (n=6 in the 300 mg tepotinib group; n=12 in the 500 mg tepotinib group) and 55 patients in phase 2 (n=31 in the tepotinib plus gefitinib group; n=24 in the chemotherapy group). No dose-limiting toxicities were observed in phase 1b, so tepotinib 500 mg was used as the recommended phase 2 dose. In phase 2, survival outcomes were similar between groups: median PFS was 4·9 months in the tepotinib plus gefitinib group (90% CI 3·9-6·9) versus 4·4 months in the chemotherapy group (90% CI 4·2-6·8; hazard ratio [HR] 0·67, 90% CI 0·35-1·28). Median OS was 17·3 months in the tepotinib plus gefitinib group (12·1-37·3) versus 18·7 months in the chemotherapy group (15·9-20·7; HR 0·69, 0·34-1·41). PFS and OS were longer with tepotinib plus gefitinib than with chemotherapy in patients with high (IHC3+) MET overexpression (n=34; median PFS 8·3 months [4·1-16·6] vs 4·4 months [4·1-6·8]; HR 0·35, 0·17-0·74; median OS 37·3 months [90% CI 24·2-37·3] vs 17·9 months [12·0-20·7]; HR 0·33, 0·14-0·76) or MET amplification (n=19; median PFS 16·6 months [8·3-not estimable] vs 4·2 months [1·4-7·0]; HR 0·13, 0·04-0·43; median OS 37·3 months [90% CI not estimable] vs 13·1 months [3·25-not estimable]; HR 0·08, 0·01-0·51). The most frequent treatment-related grade 3 or worse adverse events were increased amylase (5 [16%] of 31 patients) and lipase (4 [13%]) concentrations in the tepotinib plus gefitinib group and anaemia (7 [30%] of 23 patients) and decreased neutrophil count (3 [13%]) in the chemotherapy group.

Interpretation: Despite early study termination, in a preplanned subgroup analysis, our findings suggest improved anti activity for tepotinib plus gefitinib compared with standard chemotherapy in patients with EGFR-mutant NSCLC and MET amplification, warranting further exploration.

Funding: Merck KGaA.
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http://dx.doi.org/10.1016/S2213-2600(20)30154-5DOI Listing
November 2020

Tepotinib in Non-Small-Cell Lung Cancer with Exon 14 Skipping Mutations.

N Engl J Med 2020 09 29;383(10):931-943. Epub 2020 May 29.

From Memorial Sloan Kettering Cancer Center, New York (P.K.P.); the Oncology Department, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (E.F.), and Dr. Rosell Oncology Institute, Dexeus University Hospital, Quirónsalud Group (S.V.), Barcelona; Centre Hospitaliere Universitaire (CHU) Bordeaux, Service des Maladies Respiratoires, Bordeaux (R.V.), Université de Lille, CHU Lille, Thoracic Oncology Department, Centre National de la Recherche Scientifique, INSERM, Institut Pasteur de Lille, UMR9020-UMR-S 1277-Canther, Lille (A.B.C.), CHU de Toulouse, Institut Universitaire du Cancer de Toulouse, Université Paul Sabatier, Toulouse (J.M.), and Institut de Cancérologie de l'Ouest Rene Gauducheau Centre, Saint-Herblain (H. Senellart) - all in France; Saitama Cancer Center, Saitama (H. Sakai), and the Department of Thoracic Oncology, Kanagawa Cancer Center, Yokohama (T.K.) - both in Japan; the Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan (M.C.G.), and the Department of Surgery, Oncology and Gastroenterology, University of Padua and Oncologia Medica 2, Istituto Oncologico Veneto, IRCCS, Padua (P.C.) - both in Italy; Antwerp University Hospital, Edegem, Belgium (J.V.M., J.R.); Asklepios Lung Clinic, Munich-Gauting (N.R.), Pius Hospital Oldenburg, University Medicine Oldenburg, Oldenburg (F.G.), Translational Medicine, Department of Bioinformatics (D.J.), Translational Innovation Platform, Oncology (C.S.), the Department of Biostatistics (R.B.), Translational Medicine, Department of Clinical Biomarkers and Companion Diagnostics (J. Straub), and Global Clinical Development (A.J., J. Scheele), Merck, Darmstadt - all in Germany; the Department of Lung Cancer and Thoracic Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland (D.K.); Yonsei Cancer Center, Yonsei University College of Medicine, Seoul (B.C.C.), the Center for Lung Cancer, National Cancer Center, Goyang (J.-Y.H.), and Chonnam National University Medical School and Hwasun Hospital, Hwasun (Y.-C.K.) - all in South Korea; Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago (J.D.P.); the Department of Medicine, Vanderbilt Ingram Cancer Center, Nashville (L.H.); the Faculty of Medicine, School of Medicine, National Yang-Ming University (G.-C.C.), the Division of Chest Medicine, Department of Internal Medicine, Tri-service General Hospital, National Defense Medical Center (C.-L.T.), National Taiwan University Hospital (J.C.-H.Y.), and the Department of Chest Medicine, Taipei Veterans General Hospital, and School of Medicine, National Yang-Ming University (Y.-M.C.), Taipei, and the Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung (G.-C.C.) - both in Taiwan; the Department of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam (E.F.S.), and the Department of Pulmonology, University of Groningen and University Medical Center Groningen, Groningen (A.J.W.) - both in the Netherlands; and M.D. Anderson Cancer Center, University of Texas, Houston (J.V.H., X.L.).

Background: A splice-site mutation that results in a loss of transcription of exon 14 in the oncogenic driver occurs in 3 to 4% of patients with non-small-cell lung cancer (NSCLC). We evaluated the efficacy and safety of tepotinib, a highly selective MET inhibitor, in this patient population.

Methods: In this open-label, phase 2 study, we administered tepotinib (at a dose of 500 mg) once daily in patients with advanced or metastatic NSCLC with a confirmed exon 14 skipping mutation. The primary end point was the objective response by independent review among patients who had undergone at least 9 months of follow-up. The response was also analyzed according to whether the presence of a exon 14 skipping mutation was detected on liquid biopsy or tissue biopsy.

Results: As of January 1, 2020, a total of 152 patients had received tepotinib, and 99 patients had been followed for at least 9 months. The response rate by independent review was 46% (95% confidence interval [CI], 36 to 57), with a median duration of response of 11.1 months (95% CI, 7.2 to could not be estimated) in the combined-biopsy group. The response rate was 48% (95% CI, 36 to 61) among 66 patients in the liquid-biopsy group and 50% (95% CI, 37 to 63) among 60 patients in the tissue-biopsy group; 27 patients had positive results according to both methods. The investigator-assessed response rate was 56% (95% CI, 45 to 66) and was similar regardless of the previous therapy received for advanced or metastatic disease. Adverse events of grade 3 or higher that were considered by investigators to be related to tepotinib therapy were reported in 28% of the patients, including peripheral edema in 7%. Adverse events led to permanent discontinuation of tepotinib in 11% of the patients. A molecular response, as measured in circulating free DNA, was observed in 67% of the patients with matched liquid-biopsy samples at baseline and during treatment.

Conclusions: Among patients with advanced NSCLC with a confirmed exon 14 skipping mutation, the use of tepotinib was associated with a partial response in approximately half the patients. Peripheral edema was the main toxic effect of grade 3 or higher. (Funded by Merck [Darmstadt, Germany]; VISION ClinicalTrials.gov number, NCT02864992.).
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http://dx.doi.org/10.1056/NEJMoa2004407DOI Listing
September 2020

The promise of selective MET inhibitors in non-small cell lung cancer with MET exon 14 skipping.

Cancer Treat Rev 2020 Jul 9;87:102022. Epub 2020 Apr 9.

Medical Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain. Electronic address:

Dysregulated activation of the MET tyrosine kinase receptor is implicated in the development of solid tumors and can arise through several mechanisms, including gene amplification, overexpression of the receptor and/or its ligand hepatocyte growth factor (HGF), and the acquisition of activating mutations. The most common activating mutations cause exon 14 to be skipped during MET mRNA splicing. This in-frame deletion, known as MET exon 14, results in production of a shortened receptor that lacks a juxtamembrane domain but retains affinity for HGF. However, the negative regulatory function located within this protein sequence is lost, leading to receptor accumulation on the cell surface and prolonged activation by HGF. MET mutations causing exon 14 skipping appear to be true oncogenic drivers and occur in patients and tumors with distinct characteristics. Increasing evidence suggests that tumors carrying such mutations are sensitive to MET inhibition, raising the hope that selective MET inhibitors will provide patients with optimal anticancer activity with minimal toxicity. We discuss the prospects for selective MET inhibitors in the treatment of non-small cell lung cancer harboring MET exon 14 skipping.
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http://dx.doi.org/10.1016/j.ctrv.2020.102022DOI Listing
July 2020

Defining vulnerability in European pregnant women, a Delphi study.

Midwifery 2020 Jul 5;86:102708. Epub 2020 Apr 5.

Research Center Innovations in Care, Rotterdam University of Applied Sciences, Rochussenstraat 198, Rotterdam 3015 EK, the Netherlands. Electronic address:

Objective: Vulnerability among pregnant women is an important and complex theme in the everyday practice of midwives. Exchanging knowledge and best practices about vulnerability between midwives in Europe can contribute to improving the knowledge and skills of midwives and as a result improve the care for vulnerable pregnant women. We therefore start a consortium with midwives, midwifery teachers, researchers and students from organizations of seven European cities with the aim to exchange knowledge and best practices concerning vulnerable pregnant women between midwives. To be able to effectively exchange knowledge and best practices, our consortium started with this study focuses on establishing a mutual definition of vulnerable pregnant women. Therefore, the aim of this study is to develop a mutual definition of vulnerable pregnant women and to identify aspects related to vulnerability.

Design: Delphi study with four rounds: (1) gathering existing knowledge from literature and definitions used by partners of the consortium, (2) and (3) two survey rounds and (4) an in-person consensus meeting.

Setting: Consortium of midwives, midwifery teachers, researchers and students from Antwerp (Belgium), Ghent (Belgium), Turku (Finland), Milan (Italy), Piła (Poland), Lisbon (Portugal) and Rotterdam (The Netherlands) PARTICIPANTS: We included all consortium members in the Delphi study.

Findings: Various aspects related to vulnerability and appropriate definitions were identified during the Delphi rounds. Consensus about the aspects related to vulnerability and the definition of vulnerable pregnant women was reached during the final consensus meeting. A vulnerable pregnant woman was defined as a woman who is threatened by physical, psychological, cognitive and/or social risk factors in combination with lack of adequate support and/or adequate coping skills.

Key Conclusion: We reached consensus about a mutual definition of vulnerable pregnant women and aspects related to vulnerability within this consortium. The Delphi approach led to interesting discussions and was a valuable method to define the concept of vulnerable pregnant women within our project .

Implications For Practice: In order to accomplish a project that aimed to improve care for vulnerable pregnant women it was important to first identify the population of vulnerable pregnant women with a mutual definition.
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http://dx.doi.org/10.1016/j.midw.2020.102708DOI Listing
July 2020

Prevalence of benign osseous lesions of the spine and association with spinal pain in the general population in whole body MRI.

PLoS One 2019 9;14(9):e0219846. Epub 2019 Sep 9.

Institute for Community Medicine, Ernst-Moritz-Arndt University of Greifswald, Greifswald, Germany.

Background: Benign osseous lesions of the spine are common but precise population prevalence estimates are lacking. Our study aimed to provide the first population-based prevalence estimates and examine association with back and neck pain.

Materials And Methods: We used data from the population-based Study of Health in Pomerania (SHIP). Whole-body MRI examinations (1.5 Tesla: T1, T2, and TIRM weightings) were available from 3,259 participants. Readings of the spinal MRI images were conducted according to a standardized protocol by a single reader (JS). The intra-rater reliability was greater than Kappa values of 0.98. Pain measures included the seven-day prevalence of spine pain and neck pain, and average spine pain intensity due to spine pain during the past three months.

Results: We found 1,200 (36.8%) participants with at least one osseous lesion (2,080 lesions in total). Osseous lesions were less common in men than in women (35.5% vs 38.9%; P = .06). The prevalence of osseous lesions was highest at L2 in both sexes. The prevalence of osseous lesions increased with age. Up to eight osseous lesions were observed in a single subject. Hemangioma (28%), and lipoma (13%) occurred most often. Sclerosis (1.7%), aneurysmal bone cysts (0.7%), and blastoma (0.3%) were rare. Different osseous lesions occurred more often in combination with each other. The association with back or neck pain was mostly negligible.

Conclusion: Osseous lesions are common in the general population but of no clinical relevance for spinal pain. The prevalence of osseous lesions varied strongly across different regions of the spine and was also associated with age and gender. Our population-based data offer new insights and assist in judging the relevance of osseous lesions observed on MRIs of patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0219846PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6733514PMC
March 2020

Overstaging: A Challenge in Rectal Cancer Treatment.

Visc Med 2018 Aug 31;34(4):301-306. Epub 2018 Jul 31.

Clinic of General, Visceral, and Transplantion Surgery, University of Ulm, Ulm, Germany.

Background: Preoperative staging, including computed tomography (CT), magnetic resonance imaging (MRI), and endoscopic ultrasound (EUS), is decisive to envisage the therapeutic concept for rectal cancer (RC). Overstaging may subject the patient to neoadjuvant therapy that does not improve survival but may lead to therapy-associated morbidity.

Methods: This study retrospectively compares and values EUS, CT, and MRI in Union Internationale Contre le Cancer (UICC) stage I-III RC with a focus on overstaging. RC patients receiving primary operation only at the University Clinic Ulm were analyzed. The therapeutic relevance of preoperative staging was determined by comparison with postoperative pathological workup.

Results: 244 examinations in 184 RC patients (EUS: n = 63, CT: n = 143, MRI: n = 38) revealed therapy-relevant overstaging into the T3/4 category in 10 (16%) EUS, 18 (13%) CT, and 10 (26%) MRI cases. Patients were upgraded to the N+ category in 13 (21%) EUS, 29 (20%) CT, and 11 (29%) MRI cases. As a result, UICC stages II and III turned out to be overstaged in 13 (21%) EUS, 18 (13%) CT, and 10 (26%) MRI cases.

Conclusion: More than 10% therapy-relevant overstaging by any method represents a major challenge for modern RC therapy. Physicians should scrupulously consider this fact in their treatment considerations to avoid overtreatment.
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http://dx.doi.org/10.1159/000488652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6189530PMC
August 2018

Long-term follow-up of patients with relapsed or refractory non-Hodgkin's lymphoma receiving allogeneic stem cell transplantation.

Bone Marrow Transplant 2016 11 13;51(11):1527-1529. Epub 2016 Jun 13.

Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus, Dresden, Germany.

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http://dx.doi.org/10.1038/bmt.2016.165DOI Listing
November 2016

Population Pharmacokinetics and Target Attainment of Ertapenem in Plasma and Tissue Assessed via Microdialysis in Morbidly Obese Patients after Laparoscopic Visceral Surgery.

Antimicrob Agents Chemother 2017 01 27;61(1). Epub 2016 Dec 27.

Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, Florida, USA.

Ertapenem provides broad-spectrum activity against many pathogens, and its use is relevant for the prophylaxis and treatment of infections in morbidly obese patients undergoing surgery. However, its pharmacokinetics and tissue penetration in these patients are not well defined. We assessed the population pharmacokinetics and target attainment for ertapenem in the plasma, subcutaneous tissue, and peritoneal fluid of morbidly obese patients. Six female patients (body mass index, 43.7 to 55.9 kg/m) received 1,000 mg ertapenem as 15-min infusions at 0 and 26 h. On day 2, the unbound ertapenem concentrations in plasma, subcutaneous tissue, and peritoneal fluid were measured by microdialysis; total plasma concentrations were additionally quantified. The probability of attaining a target of an unbound ertapenem concentration above the MIC for at least 40% of the dosing interval was predicted via Monte Carlo simulations. The population pharmacokinetic model contained two disposition compartments and simultaneously described all concentrations. For unbound ertapenem, total clearance was 12.3 liters/h (coefficient of variation, 21.6% for between-patient variability) and the volume of distribution at steady state was 57.8 liters in patients with a 53-kg fat-free mass. The area under the concentration-time curve (AUC) for ertapenem was 49% lower in subcutaneous tissue and 25% lower in peritoneal fluid than the unbound AUC in plasma. Tissue penetration was rapid (equilibration half-life, <15 min) and was variable in subcutaneous tissue. Short-term ertapenem infusions (1,000 mg every 24 h) achieved robust (>90%) target attainment probabilities for MICs of up to 1 mg/liter in plasma, 0.25 to 0.5 mg/liter in subcutaneous tissue, and 0.5 mg/liter in peritoneal fluid. Ertapenem presents an attractive choice for many pathogens relevant to morbidly obese patients undergoing surgery. (This study has been registered at ClinicalTrials.gov under identifier NCT01407965.).
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http://dx.doi.org/10.1128/AAC.00952-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5192102PMC
January 2017

Survival and Prognostic Factors of Colorectal Liver Metastases After Surgical and Nonsurgical Treatment.

Clin Colorectal Cancer 2016 12 7;15(4):e183-e192. Epub 2016 May 7.

Clinic of General and Visceral Surgery, University of Ulm, Ulm, Germany. Electronic address:

Objective: Colorectal cancer is one leading cause of cancer-related death worldwide, and distant metastases determine an unfavorable prognosis. Surgical resection of colorectal liver metastases (CRLM) improves survival and provides the chance for cure. The aim of this study was to prospectively analyze the outcome of patients with CRLM in a population-based manner, and thereby, to compare the prognosis of patients undergoing resection with those receiving nonsurgical treatment. Moreover, we set out to identify and confirm important prognostic factors after resection of CRLM.

Patients And Methods: We analyzed the outcome of 506 patients diagnosed with CRLM in our institution from 1996 to 2011. Survival and the impact of clinical and pathologic factors were analyzed by univariate analysis. Important independent prognostic factors were analyzed by multivariate analysis.

Results: The 5-year overall survival rate (5y-OSR) for patients receiving resection of CRLM (n = 152) was 46% (95% confidence interval (CI), 37%-54%) compared with a 5y-OSR of 6% (95% CI, 4%-9%) for patients treated nonsurgically (n = 354). There was no perioperative mortality. Multivariate analysis revealed, among other factors, good performance status of the patient (low American Society of Anesthesiologists score), the absence of extrahepatic metastases, < 5 metastatic lesions, and a tumor-free resection margin (R0) as important, independent prognostic factors. Importantly, repeated hepatic resections of CRLM performed in 13 patients were associated with an excellent outcome (5y-OSR, 47%; 95% CI, 17%-72%).

Conclusion: Surgical resection, which can be performed with tolerable site-effects, is the first choice for patients diagnosed with metachronous and synchronous CRLM. Of note, repeated resections should be advised in recurrent intrahepatic colorectal cancer whenever possible.
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http://dx.doi.org/10.1016/j.clcc.2016.04.007DOI Listing
December 2016

Bispecific T-Cell Engager (BiTE) Antibody Construct Blinatumomab for the Treatment of Patients With Relapsed/Refractory Non-Hodgkin Lymphoma: Final Results From a Phase I Study.

J Clin Oncol 2016 Apr 16;34(10):1104-11. Epub 2016 Feb 16.

Maria-Elisabeth Goebeler, Stefan Knop, Max S. Topp, Hermann Einsele, and Ralf C. Bargou, Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg; Andreas Viardot, University Ulm; Peter Kufer, Gerhard Zugmaier, Matthias Klinger, Andreas Wolf, Margit Schmidt, and Patrick A. Baeuerle, Amgen Research (Munich); Brigitte Dorsch, Metronomia Clinical Research, Munich; Richard Noppeney, University of Essen Medical Center, Essen; Georg Hess, Johannes Gutenberg-University, Mainz; Stefan Kallert and Andreas Mackensen, University of Erlangen Medical Center, Erlangen; Kathrin Rupertus and Lothar Kanz, University of Tübingen Medical Center, Tübingen; Martin Libicher, Diakoniekrankenhaus Schwäbisch-Hall, Schwäbisch-Hall; Jürgen Scheele, University of Freiburg Medical Center; Eugen Leo, LEOConsulting, Freiburg, Germany; and Dirk Nagorsen and Beate D. Quednau, Amgen, Thousand Oaks, CA.

Purpose: Blinatumomab is a CD19/CD3 BiTE (bispecific T-cell engager) antibody construct for the treatment of Philadelphia chromosome-negative acute B-lymphoblastic leukemia. We evaluated blinatumomab in relapsed/refractory B-cell non-Hodgkin lymphoma (NHL).

Patients And Methods: This 3 + 3 design, phase I dose-escalation study determined adverse events and the maximum tolerated dose (MTD) of continuous intravenous infusion blinatumomab in patients with relapsed/refractory NHL. Blinatumomab was administered over 4 or 8 weeks at seven different dose levels (0.5 to 90 μg/m(2)/day). End points were incidence of adverse events, pharmacokinetics, pharmacodynamics, and overall response rate.

Results: Between 2004 and 2011, 76 heavily pretreated patients with relapsed/refractory NHL, who included 14 with diffuse large B-cell lymphoma, were enrolled; 42 received treatment in the formal dose-escalation phase. Neurologic events were dose limiting, and 60 μg/m(2)/day was established as the MTD. Thirty-four additional patients were recruited to evaluate antilymphoma activity and strategies for mitigating neurologic events at a prespecified MTD. Stepwise dosing (5 to 60 μg/m(2)/day) plus pentosan polysulfate SP54 (n = 3) resulted in no treatment discontinuations; single-step (n = 5) and double-step (n = 24) dosing entailed two and seven treatment discontinuations due to neurologic events, respectively. Grade 3 neurologic events occurred in 22% of patients (no grade 4/5). Among patients treated at 60 μg/m(2)/day (target dose; n = 35), the overall response rate was 69% across NHL subtypes and 55% for diffuse large B-cell lymphoma (n = 11); median response duration was 404 days (95% CI, 207 to 1,129 days).

Conclusion: In this phase I study of relapsed/refractory NHL, continuous infusion with CD19-targeted immunotherapy blinatumomab at various doses and schedules was feasible, with an MTD of 60 μg/m(2)/day. Single-agent blinatumomab showed antilymphoma activity.
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http://dx.doi.org/10.1200/JCO.2014.59.1586DOI Listing
April 2016

Population Pharmacokinetics and Target Attainment of Meropenem in Plasma and Tissue of Morbidly Obese Patients after Laparoscopic Intraperitoneal Surgery.

Antimicrob Agents Chemother 2015 Oct 27;59(10):6241-7. Epub 2015 Jul 27.

Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), Parkville, Victoria, Australia.

Meropenem serves as a clinically important, broad-spectrum antibiotic. While meropenem is commonly used in obese patients, its pharmacokinetics in this patient group is not well known. Our aim was to characterize the population pharmacokinetics and target attainment in plasma, subcutaneous tissue, and peritoneal fluid for meropenem in morbidly obese patients. Four doses of 1g meropenem were given as 15-min infusions every 8 h to five morbidly obese patients (body mass index [BMI], 47.6 to 62.3 kg/m(2)). After the fourth dose, serial meropenem concentrations were determined in plasma and, via microdialysis, in subcutaneous tissue and peritoneal fluid. All concentrations were analyzed simultaneously via population modeling, and target attainment probabilities predicted via Monte Carlo simulations using the target of unbound meropenem concentrations above the MIC for at least 40% of the dosing interval. For patients with 53 kg fat-free mass, total clearance was 18.7 liters/h and volume of distribution at steady state was 27.6 liters. The concentrations in subcutaneous tissue and peritoneal fluid largely paralleled those in plasma (equilibration half-life, <30 min). The area under the curve (AUC) in subcutaneous tissue divided by the plasma AUC had a mean of 0.721. For peritoneal fluid, this AUC ratio had a mean of 0.943. Target attainment probabilities were >90% after 1 g meropenem every 8 h as a 15-min infusion for MICs of up to 2 mg/liter in plasma and peritoneal fluid and 0.5 mg/liter in subcutaneous tissue. Meropenem pharmacokinetics in plasma and peritoneal fluid of obese patients was predictable, but subcutaneous tissue penetration varied greatly. (This study has been registered at ClinicalTrials.gov under registration no. NCT01407965.).
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http://dx.doi.org/10.1128/AAC.00259-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4576127PMC
October 2015

Prevalence and "Red Flags" Regarding Specified Causes of Back Pain in Older Adults Presenting in General Practice.

Phys Ther 2016 Mar 16;96(3):305-12. Epub 2015 Jul 16.

P.A.J. Luijsterburg, PhD, Department of General Practice, Erasmus MC, University Medical Center.

Background: In a small proportion of patients experiencing unspecified back pain, a specified underlying pathology is present.

Objective: The purposes of this study were: (1) to identify the prevalence of physician-specified causes of back pain and (2) to assess associations between "red flags" and vertebral fractures, as diagnosed by the patients' general practitioner (GP), in older adults with back pain.

Methods: The Back Complaints in the Elders (BACE) study is a prospective cohort study. Patients (aged >55 years) with back pain were included when consulting their GP. A questionnaire was administered and a physical examination and heel bone densitometry were performed, and the results determined back pain and patient characteristics, including red flags. Participants received a radiograph, and reports were sent to their GP. The final diagnoses established at 1 year were collected from the GP's patient registry.

Results: Of the 669 participants included, 6% were diagnosed with a serious underlying pathology during the 1-year follow-up. Most of these participants (n=33, 5%) were diagnosed with a vertebral fracture. Multivariable regression analysis showed that age of ≥75 years, trauma, osteoporosis, a back pain intensity score of ≥7, and thoracic pain were associated with a higher chance of getting the diagnosis of a vertebral fracture. Of these variables, trauma showed the highest positive predictive value for vertebral fracture of 0.25 (95% confidence interval=0.09, 0.41) and a positive likelihood ratio of 6.2 (95% confidence interval=2.8, 13.5). A diagnostic prediction model including the 5 red flags did not increase these values.

Limitations: Low prevalence of vertebral fractures could have led to findings by chance.

Conclusions: In these older adults with back pain presenting in general practice, 6% were diagnosed with serious pathology, mainly a vertebral fracture (5%). Four red flags were associated with the presence of vertebral fracture.
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http://dx.doi.org/10.2522/ptj.20140525DOI Listing
March 2016

Quality of Life After Sphincter-Preserving Rectal Cancer Resection.

Clin Colorectal Cancer 2015 Dec 6;14(4):e33-40. Epub 2015 Jun 6.

Clinic of General and Visceral Surgery, University of Ulm, Ulm, Germany. Electronic address:

Background: With an increasing number of cancer survivors quality of life (QoL) becomes more and more important in the treatment of rectal cancer (RC). QoL after sphincter-preserving anterior resection (AR), however, was found nonsuperior to abdominoperineal resection. The aim of our study was to evaluate QoL after AR compared with colon cancer patients after right hemicolectomy (CC) and healthy lay persons without history of cancer (HL) in long-term follow-up.

Patients And Methods: Consecutive alive RC patients (n = 293) who received an AR between 1998 and 2008 were included. CC patients (n = 201) and HL of the same age were used as a surgical and a nonsurgical control group, respectively. QoL was assessed using European Organization of Research and Treatment of Cancer questionnaires QLQ-C 30 and -CR 38.

Results: Questionnaires from 116 RC patients, 105 CC patients, and 103 HL were evaluable with a median time after surgery of 5 years. The global health status did not differ. Social functioning, future perspectives, and financial difficulties tended to poorer scores in the cancer groups. Physical functioning was better in RC and CC patients compared with HL. Defecation problems and diarrhea were more frequent in RC patients (P < .05). An additional open question revealed a median stool frequency of 3, 2, and 1 per day for RC, CC, and HL, respectively. Defecation problems were more frequent in RC patients who received radiation therapy (P < .05).

Conclusion: Diarrhea and defecation problems impaired QoL after AR for RC, which was worsened after radiation therapy. To improve QoL of RC patients in the future, physicians have to focus on minimization of gastrointestinal side effects while optimizing surgical reconstruction.
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http://dx.doi.org/10.1016/j.clcc.2015.05.012DOI Listing
December 2015

Brain metastases in gastrointestinal cancers: is there a role for surgery?

Int J Mol Sci 2014 Sep 22;15(9):16816-30. Epub 2014 Sep 22.

Clinic of General and Visceral Surgery, University Hospital Ulm, Albert-Einstein-Allee 23, Ulm 89071, Germany.

About 10% of all cancer patients will develop brain metastases during advanced disease progression. Interestingly, the vast majority of brain metastases occur in only three types of cancer: Melanoma, lung and breast cancer. In this review, we focus on summarizing the prognosis and impact of surgical resection of brain metastases originating from gastrointestinal cancers such as esophageal, gastric, pancreatic and colorectal cancer. The incidence of brain metastases is <1% in pancreatic and gastric cancer and <4% in esophageal and colorectal cancer. Overall, prognosis of these patients is very poor with a median survival in the range of only months. Interestingly, a substantial number of patients who had received surgical resection of brain metastases showed prolonged survival. However, it should be taken into account that all these studies were not randomized and it is likely that patients selected for surgical treatment presented with other important prognostic factors such as solitary brain metastases and exclusion of extra-cranial disease. Nevertheless, other reports have demonstrated long-term survival of patients upon resection of brain metastases originating from gastrointestinal cancers. Thus, it appears to be justified to consider aggressive surgical approaches for these patients.
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http://dx.doi.org/10.3390/ijms150916816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4200819PMC
September 2014

Analgesic use in older adults with back pain: the BACE study.

Pain Med 2014 Oct 4;15(10):1704-14. Epub 2014 Aug 4.

Department of General Practice, Erasmus University Medical Center, Rotterdam, The Netherlands.

Background: Older patients with back pain are more likely to visit their general practitioner (GP) and are more likely to be prescribed analgesics.

Objective: To assess analgesic use in older adults with back pain in general practice.

Methods: The BACE study in the Netherlands is a prospective cohort study. Patients (aged >55 years) with back complaints were recruited when consulting their GP or shortly thereafter. Measurements took place at baseline and at 3- and 6-month follow-up. For medication use, patients were asked if they had used any medication for their back pain in the previous 3 months and, if so, to specify the medication name, dosage used, frequency of usage, and whether the medication was prescribed or purchased over the counter.

Results: Of the 1,402 patients who were approached to enter the study, 675 were included. Of these patients, 484 (72%) reported medication use at baseline. Nonsteroidal anti-inflammatory drugs (NSAIDs) (57%) were more often used than paracetamol (49%). Paracetamol was mostly obtained over the counter (69%), and NSAIDs were mostly obtained by prescription (85%). At baseline, patients with severe pain (numerical rating scale score ≥7) used more paracetamol, opioids, and muscle relaxants. Patients with chronic pain (back pain >3 months) used more paracetamol, while patients with a shorter duration of pain used more NSAIDs. During follow-up there was an overall decline in medication use; however, at 3- and 6-month follow-up, 36% and 30% of the patients, respectively, still used analgesics.

Conclusions: In these older adults consulting their GP with back pain, 72% used analgesics at baseline. Despite a decrease in medication use during follow-up, at 3 and 6 months a considerable proportion still used analgesics.
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http://dx.doi.org/10.1111/pme.12515DOI Listing
October 2014

Chondroid hamartoma of the liver.

GMS Interdiscip Plast Reconstr Surg DGPW 2014 17;3:Doc16. Epub 2014 Dec 17.

Clinic of General and Visceral Surgery, University of Ulm, Ulm, Germany.

A 60-year-old patient presented with a solitary mass within the right hepatic lobe. Diagnostic imaging revealed a solid tumor on the diameter of 3 cm. In absence of any extrahepatic manifestation and based on FNAC findings the lesion was classisfied a primary hepatic chondroid sarcoma. However, after right hemihepatectomy histologic assessment resulted the final diagnosis of a benign chondroid hamartoma. Our findings add another variant to the versatile phenotype of liver hamartoma.
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http://dx.doi.org/10.3205/iprs000057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4582503PMC
October 2015

Massive gastric dilatation caused by eating binges demanding surgical intervention: a case report.

GMS Interdiscip Plast Reconstr Surg DGPW 2014 3;3:Doc09. Epub 2014 Nov 3.

Clinic of General and Visceral Surgery, University of Ulm, Germany.

The clinical picture of an acute abdomen is frequently encountered in emergency medicine. In most cases abdominal pathologies underlie this condition, however, also extra-abdominal diseases may present or cause an acute abdomen. The fact that this condition is potentially life-threatening highlights the importance of instant action. Here, we report on the case of a young woman that presented with an acute abdomen in our clinic. Imaging revealed a massively distended stomach reaching the lesser pelvis. Initially, the etiology for the gastric dilatation remained unsolved. On the same day we performed an explorative laparotomy in which massive amounts of clotted, undigested food was recovered via a gastrotomy. Postoperatively, upon psychiatric consultation, an eating disorder with daily eating binges could be revealed as being the cause for the acute and dramatic gastric dilatation. The patient fully recovered from surgery and psychiatric co-treatment was initiated. This unique case report demonstrates how a psychiatric condition may lead to an acute abdomen, however, it also emphasizes the importance of prompt diagnosis and adequate therapy to avoid complications and allowing for full recovery.
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http://dx.doi.org/10.3205/iprs000050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4582510PMC
October 2015

Back complaints in older adults: prevalence of neuropathic pain and its characteristics.

Pain Med 2013 Nov 4;14(11):1664-72. Epub 2013 Oct 4.

Department of General Practice, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.

Objective: Neuropathic symptoms are reported in 16-55.6% of patients with back pain. Studies were performed in various populations; however, none focused on older adults. The aim of the study was to assess prevalence of neuropathic pain in older adults with back pain.

Methods: Prevalence of neuropathic pain, measured with the Dolour Neuropathique en 4 questions (DN4), was assessed in the Back Complaints in the Elders study (Netherlands). Patients (>55 years) consulting their general practitioner with a new episode of back complaints were included. Two DN4-versions were used: one based on interview plus physical examination, the other based on interview alone. In the interview plus physical examination version, patients' and complaint characteristics were compared between groups with different scores (0, 1, 2, 3, and ≥4). The DN4 interview-version compared patients with negative and positive scores.

Results: Of the 261 included patients available for analysis were 250 patients (95.8%) with the DN4 interview plus physical examination, and 259 patients (99.2%) with the DN4 interview. In DN4 interview plus physical examination (N = 250), five patients (2%) scored positive (score ≥4). Higher score was associated with pain radiating below the knee (P < 0.001) and use of paracetamol (P = 0.02). In DN4 interview (N = 259), 29 (11.2%) patients scored positive (score ≥3). Positive score was associated with higher body mass index (P = 0.01), pain radiating below the knee (P = 0.001), and use of paracetamol (P = 0.002).

Conclusions: In older adults with back pain presenting with a new episode in primary care, prevalence of neuropathic pain is low and seems to be associated with pain radiating below the knee, use of paracetamol, and higher body mass index.
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http://dx.doi.org/10.1111/pme.12232DOI Listing
November 2013

Direct access to physical therapy for patients with low back pain in the Netherlands: prevalence and predictors.

Phys Ther 2014 Mar 3;94(3):363-70. Epub 2013 Oct 3.

J. Scheele, PhD, Department of General Practice, Erasmus MC, University Medical Center, PO Box 2040, 3000 CA, Rotterdam, the Netherlands.

Background: In the Netherlands, direct access to physical therapy was introduced in 2006. Although many patients with back pain visit physical therapists through direct access, the frequency and characteristics of episodes of care are unknown.

Objective: The purposes of this study were: (1) to investigate the prevalence of direct access to physical therapy for patients with low back pain in the Netherlands from 2006 to 2009, (2) to examine associations between mode of access (direct versus referral) and patient characteristics, and (3) to describe the severity of the back complaints at the beginning and end of treatment for direct access and referral-based physical therapy.

Design: A cross-sectional study was conducted using registration data of physical therapists obtained from a longitudinal study.

Method: Data were used from the National Information Service for Allied Health Care, a registration network of Dutch physical therapists. Mode of access (direct or referral) was registered for each episode of physical therapy care due to back pain from 2006 to 2009. Logistic regression analysis was used to explore associations between mode of access and patient/clinical characteristics.

Results: The percentage of episodes of care for which patients with back pain directly accessed a physical therapist increased from 28.9% in 2006 to 52.1% in 2009. Characteristics associated with direct access were: middle or higher education level (odds ratio [OR]=1.3 and 2.0, respectively), previous physical therapy care (OR=1.7), recurrent back pain (OR=1.7), duration of back pain <7 days (OR=4.2), and age >55 years (OR=0.6).

Limitations: The study could not compare outcomes of physical therapy care by mode of access because this information was not registered from the beginning of data collection and, therefore, was missing for too many cases.

Conclusions: Direct access was used for an increasing percentage of episodes of physical therapy care in the years 2006 to 2009. Patient/clinical characteristics associated with the mode of access were education level, recurrent back pain, previous physical therapy sessions, and age.
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http://dx.doi.org/10.2522/ptj.20120330DOI Listing
March 2014

Characteristics of older patients with back pain in general practice: BACE cohort study.

Eur J Pain 2014 Feb 19;18(2):279-87. Epub 2013 Jul 19.

Department of General Practice, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.

Background: Although back pain is common among older people, limited information is available about the characteristics of these patients in primary care. Earlier research suggests that the severity of back symptoms increases with older age.

Methods: Patients aged >55 years visiting a general practitioner with a new episode of back pain were included in the BACE study. Information on patients' characteristics, characteristics of the complaint and physical examination were derived from the baseline measurement. Cross-sectional differences between patients aged >55-74 and ≥75 years were analysed using an unpaired t-test, Mann-Whitney U-test or a chi-square test.

Results: A total of 675 back pain patients were included in the BACE study, with a median age of 65 (interquartile range 60-71) years. Patients aged >55-74 years had a mean disability score (measured with the Roland Disability Questionnaire) of 9.4 [standard deviation (SD) 5.8] compared with 12.1 (SD 5.5) in patients aged ≥75 years (p ≤ 0.01). The older group reported more additional musculoskeletal disorders and more often had low bone quality (based on ultrasound measurement of the heel) than patients aged >55-74 years. Average back pain severity over the previous week showed no difference (p = 0.11) between the age groups, but severity of back pain at the moment of filling in the questionnaire was higher (p = 0.03) in the older age group.

Conclusions: In this study, older back pain patients reported more disabilities and co-morbidity. However, the clinical relevance of these differences for the course of the back pain episode in older patients remains a subject for further research.
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http://dx.doi.org/10.1002/j.1532-2149.2013.00363.xDOI Listing
February 2014

Course and prognosis of older back pain patients in general practice: a prospective cohort study.

Pain 2013 Jun 14;154(6):951-7. Epub 2013 Mar 14.

Department of General Practice, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.

The aim of the current study was to determine the course of back pain in older patients and identify prognostic factors for non-recovery at 3 months' follow-up. We conducted a prospective cohort study (the BACE study) of patients aged >55 years visiting a general practitioner (GP) with a new episode of back pain in the Netherlands. The course of back pain was described in terms of self-perceived recovery, pain severity, disability, pain medication, and GP visits at 6 weeks' and 3 months' follow-up. Prognostic factors for non-recovery at 3 months' follow-up were derived from the baseline questionnaire and physical examination. Variables with a prognostic value were identified with multivariable logistic regression analysis (method backward), and an area under the receiver operating curve (AUC) was calculated for the prognostic model. A total of 675 back pain patients (mean age 66.4 (SD 7.6) years) participated in the BACE cohort study. At 6 weeks' follow-up 64% of the patients reported non-recovery from back pain. At 3 months' follow-up 61% still reported non-recovery, but only 26% of these patients had revisited the GP. Longer duration of the back pain, severity of back pain, history of back pain, absence of radiating pain in the leg below the knee, number of comorbidities, patients' expectation of non-recovery, and a longer duration of the timed 'Up and Go' test were significantly associated with non-recovery in a multiple regression model (AUC 0.79). This information can help GPs identify older back pain patients at risk for non-recovery.
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http://dx.doi.org/10.1016/j.pain.2013.03.007DOI Listing
June 2013

Brain metastasis in pancreatic cancer.

Int J Mol Sci 2013 Feb 19;14(2):4163-73. Epub 2013 Feb 19.

Clinic of General and Visceral Surgery, University Hospital Ulm, Albert-Einstein-Allee 23, Ulm 89071, Germany.

Pancreatic cancer is a fatal disease with a 5-year survival rate below 5%. Most patients are diagnosed at an advanced tumor stage and existence of distant metastases. However, involvement of the central nervous system is rare in pancreatic cancer. We retrospectively analyzed all cases of brain metastases in pancreatic cancer reported to date focusing on patient characteristics, clinical appearance, therapy and survival. Including our own, 12 cases of brain metastases originating from pancreatic cancer were identified. In three patients brain metastases were the first manifestation of pancreatic cancer. All other patients developed brain metastases during their clinical course. In most cases, the disease progressed rapidly and the patients died within weeks or months. However, two patients showed long-term survival. Of note, both patients received resection of the pancreatic cancer as well as curative resection of the metachronous brain metastases. Brain metastases in pancreatic cancer are a rare condition and usually predict a very poor prognosis. However, there is evidence that resection of brain metastases of pancreatic cancer can be immensely beneficial to patient's survival, even with the chance for cure. Therefore, a surgical approach in metastatic pancreatic cancer should be considered in selective cases.
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http://dx.doi.org/10.3390/ijms14024163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3588092PMC
February 2013

A phase I trial assessing the safety, tolerability, pharmacokinetic and pharmacodynamic characteristics of single-dose Auron Misheil therapy in healthy male subjects.

J Clin Pharm Ther 2013 Feb 14;38(1):3-11. Epub 2009 Aug 14.

Auron Healthcare GmbH, Freiburg, Germany.

Background And Objective: Auron Misheil therapy (AMT) is a combination of widely used pharmaceuticals and herbal components that has been used since the 1980s as a supportive therapy, mainly in end-stage cancer patients on a compassionate basis. This phase I study was conducted to assess the safety, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) properties of AMT in a controlled trial environment.

Methods: The study was conducted in a single rising dose, double-blind, placebo-controlled design. Three groups of eight healthy male volunteers received one of three doses of AMT (0·011, 0·033 or 0·066 mL AMT/kg body weight intramuscularly; n = 6 per group) or placebo (n = 2 per group).

Results And Discussion: Auron Misheil therapy was shown to be well tolerated, revealing no severe or serious adverse events. There were no unexpected PK or PD results for any of the three components of AMT.

Conclusions: These data provide important PK, PD and safety data for AMT, and support further controlled clinical investigation in patients with different types of cancer as an option for supportive care.
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http://dx.doi.org/10.1111/j.1365-2710.2009.01087.xDOI Listing
February 2013

The side population phenomenon enriches for designated adrenocortical progenitor cells in mice.

J Endocrinol 2012 Dec 5;215(3):383-91. Epub 2012 Oct 5.

Endocrine Research Unit, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstraße 1, D-80336 Munich, Germany.

Somatic adrenal stem cells are believed to reside in the periphery of the adrenal cortex throughout life for organ maintenance. Herein, we used the side population (SP) phenomenon to enrich for these progenitors, which made up to 0.01-0.64% of the total cell count. Microarray analysis revealed an expression profile of SP cells, which clearly differed from that of non-SP cells. However, a promising adrenal specific stem cell marker could not be identified. In vitro, SP cells could be maintained in long-term culture, whereas non-SP cells did not proliferate. After 4 weeks of culturing, immunohistochemistry revealed the expression of steroidogenic enzymes such as 3β-HSD, StAR, and P450SCC, suggesting spontaneous differentiation. Interestingly, the quantity of SP cells was significantly diminished in Pbx1 haploinsufficient mice, suggesting a stem cell deficit. By contrast, the subcapsular zone of ACTH-deficient Tpit(-/-) mice was significantly wider compared with wild-type adrenals (Tpit(-/-) 259±10.7 vs Tpit(+/-) 100±12.3%; P<0.01). Accordingly, the number of SP cells in these mice was significantly higher (Tpit(-/-) 0.45±0.16 vs Tpit(+/-) 0.13±0.04%; P<0.004). ACTH treatment of these animals reverted the subcapsular zone width and the SP fraction back to normal (130±10.2%; P=0.33 and 0.09%), providing indirect evidence for a stem cell 'arrest' in Tpit(-/-) mice and the role of ACTH in adrenocortical stem cell modulation and differentiation.
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http://dx.doi.org/10.1530/JOE-12-0393DOI Listing
December 2012

Course of back complaints in older adults: a systematic literature review.

Eur J Phys Rehabil Med 2012 Sep 23;48(3):379-86. Epub 2012 Jul 23.

Department of General Practice, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.

Background: Back pain is a common musculoskeletal complaint seen in older people. It is important to get an insight in the course of back complaints and to identify factors associated with a chronic course.

Aim: To describe the course of acute and subacute back complaints in older people (≥ 45 years) and to identify prognostic factors for developing chronic back complaints.

Design: Systematic review of the literature.

Methods: A database search was conducted in MEDLINE, EMBASE, Cochrane library, CINAHL, PsycINFO and PEDro. Cohort studies or randomized controlled trials reporting on the course of acute or subacute back complaints in older people were included. The percentage of patients that developed chronic back complaints was calculated, if possible.

Results: The search yielded 9293 potentially relevant articles. Of these, 5 studies met all inclusion criteria. At 3 months follow-up 37-40% of the patients still had back complaints. At 12 months follow-up, the percentage ranged from 26-45%. Older age was frequently reported as a prognostic factor for developing chronic back complaints of the whole study population. No prognostic factors could be retrieved for patients aged 45 years and older.

Conclusions: At 3 and 12 month follow-up, about 40% of the older people still reported back complaints. However, the heterogeneity of the studies made comparisons difficult. In order to get a clear insight in the course of back complaints in the older adult patients and to indentify prognostic factors for developing chronic back complaints in older people, high quality prospective cohort studies are needed.

Clinical Rehabilitation Impact: More than one-third of the older patients with back pain still experience complaints after 3 and 12 months.
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September 2012

Association between spinal morning stiffness and lumbar disc degeneration: the Rotterdam Study.

Osteoarthritis Cartilage 2012 Sep 12;20(9):982-7. Epub 2012 Jun 12.

Department of General Practice, Erasmus MC, University Medical Center Rotterdam, The Netherlands.

Objective: To explore the associations between spinal morning stiffness and lumbar disc degeneration (LDD).

Design: Data from a cross-sectional general population-based study (Rotterdam Study-I) were used. Intervertebral disc spaces and osteophytes of people aged ≥55 years were scored on lumbar lateral radiographs (L1-2 through L5-S1 was scored). Logistic regression analysis was used to explore associations between spinal morning stiffness and two definitions of LDD (i.e., 'narrowing' and 'osteophytes'). Spinal morning stiffness combined with low back pain and its association with LDD was also analyzed. Similar analyses were performed for knee and hip pain, morning stiffness in the legs, and radiographic knee and hip osteoarthritis (OA) in order to compare these associations with those of LDD. All analyses were adjusted for age, gender, and body mass index (BMI).

Results: Lumbar lateral radiographs were scored for 2,819 participants. Both definitions of LDD were associated with spinal morning stiffness: adjusted odds ratio (aOR) 1.3; 95% confidence interval (CI): 1.1-1.6 for 'osteophytes' and aOR 1.8; 95% CI: 1.4-2.2 for 'narrowing'. Both the odds ratios increased when spinal morning stiffness was combined with low back pain: aOR 1.5; 95% CI: 1.1-2.0 for 'osteophytes' and aOR 2.5; 95% CI: 1.9-3.4 for 'narrowing'. When morning stiffness in the legs was combined with knee or hip pain, the associations with radiographic knee or hip OA were: aOR 3.0; 95% CI: 2.1-4.1 for knee OA and aOR 3.1; 95% CI: 1.9-5.0 for hip OA.

Conclusions: Reported spinal morning stiffness is associated with LDD. The associations increased when we combined spinal morning stiffness with low back pain. The magnitude of the association for the definition 'narrowing' is similar to the association between morning stiffness in the legs and knee or hip OA.
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http://dx.doi.org/10.1016/j.joca.2012.05.011DOI Listing
September 2012

Rap1a deficiency modifies cytokine responses and MAPK-signaling in vitro and impairs the in vivo inflammatory response.

Cell Immunol 2012 Mar-Apr;276(1-2):187-95. Epub 2012 May 23.

Department of Pathology, University Medical Centre Freiburg, Freiburg, Germany.

Rap1, which is closely related to ras, plays a key role in T-cell receptor (TCR)-signaling. TCR-stimulation without costimulation leads to constitutively activated rap1, which may mediate T-cell anergy via inhibition of ras-dependent induction of extracellular signal-regulated kinases (ERK). This activation is mediated by a second protein kinase b-Raf. Rap1-GTP is thought to activate ERK in a ras-independent manner by binding b-raf. Generally, T cells do not express b-raf while they express the adaptor protein raf-1, which is usually sequestered by rap1 leading to inhibition of ras-mediated ERK activation. In this study, we demonstrate that in rap1-deficient T cells, signaling by the ERK and p38 kinases is increased following activation by different stimuli leading to increased intracellular accumulation and secretion of cytokines. In addition, in a hypersensitivity model rap1-deficient mice demonstrated reduced contact dermatitis compared to wildtype mice, demonstrating the impact of rap1-deficiency on the inflammatory response in vivo.
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http://dx.doi.org/10.1016/j.cellimm.2012.05.008DOI Listing
October 2012

Cystic teratoma of the pancreas.

Anticancer Res 2012 Mar;32(3):1075-80

Department of General, Visceral, and Transplantation Surgery, University of Ulm, Steinhoevelstrasse 9, D-89075 Ulm, Germany.

Aim: Benign cystic teratoma of the pancreas often appears to be potentially malignant in preoperative staging. The final diagnosis is generally obtained after surgical removal. Reliable prediction is mandatory for differential treatment.

Materials And Methods: A Medline query was performed for the terms cystic teratoma, dermoid cyst and pancreas. Data were analyzed for patient characteristics, clinical appearance, diagnostic findings, therapy and follow-up.

Results: Including our own, 26 cases of pancreatic cystic teratoma were identified. The majority of patients were symptomatic by unspecific gastrointestinal complaints. Up to date, imaging techniques fail at a distinct preoperative diagnosis. Surgical treatment evolved from various drainage and excision procedures into radical resection.

Conclusion: Despite the strictly benign nature of cystic teratoma, oncologic resection is mostly inevitable due to difficult preoperative diagnosis. No reliable predictive marker was found to allow for organ- or parenchyma-preserving procedures. Therefore, surgery remains the treatment of choice to exclude malignancy.
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March 2012